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The origin of equine endometrial cups. II. Invasion of the endometrium by trophoblast

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The Origin of Equine Endometrial Cups
11. INVASION OF THE ENDOMETRIUM B Y TROPHOBLAST
W. R. ALLEN, D. W.
AND R. M. MOOR
ARC U n i t of Reproductive Physiology a n d Biochemistry, Cambridge,
England and Department of A n a t o m y , Harvard Medical School,
Boston, Massachusetts 021 15
ABSTRACT
Light and electron microscopic examination of tissues fixed in
situ by perfusion of the gravid horn of the uteri of mares between 36 and 38
days of gestation revealed that the equine endometrial cups are composed of
trophoblast cells which originate from the discrete annulate portion of the foetal
membranes known as the chorionic girdle. This structure consists of closely
opposed villous projections of elongated trophoblast cells and i t becomes firmly
attached to the endometrium around the thirty-sixth day of pregnancy. The
specialized girdle cells invade and phagocytose the endometrial epithelium and
then migrate through the basal lamina into the endometrial stroma where they
develop into endometrial cup cells.
Measurement of pregnant mares serum
gonadotrophin (PMSG) concentrations in
foetal and maternal tissues of horses led
Catchpole and Lyons ('34) to postulate
that PMSG is secreted by the foetal chorion
and stored in the endometrium. Subsequent experiments have conclusively dernonstrated, however, that PMSG is manufactured by discrete endometrial outgrowths
present in the pregnant horn of the uterus
of mares between the 38th and 150th days
of gestation, the endometrial cups (Cole
and Goss, '43; Clegg, Boda and Cole, '54).
It has been widely considered in the
past that the endometrial cups are entirely
maternal in origin (Amoroso, '55; Gonzalez-Angullo and Hernandez-Jouregui, '71),
although this hypothesis has been brought
into question by the finding that foetal
genotype profoundly influences PMSG
levels in the maternal blood (Bielanski,
Ewy and Pigoniowa, '55; Clegg, Cole,
Howard and Pigon, '62; Allen, '69). Moreover, we have recently demonstrated that
the only cells which possess the capacity
to synthesize PMSG in vitro are those of
the specialized area of the allantochorion
known as the chorionic girdle (Allen and
Moor, '72).
The purpose of this paper is to describe
the origin and histogenesis of endometrial
cups at the fine-structure level.
ANAT. REC., 177: 485-502.
MATERIALS AND METHODS
In order to maintain the delicate anatomical relationship between foetal and
maternal tissues, our experiments were
carried out upon material fixed in situ by
perfusion of the uterus.
Laparotomies were performed upon
three Welsh Pony mares at 36, 37 and 38
days of gestation respectively (day of ovulation = day 0). The anaesthetized animals were positioned on their backs and
a large flap of the ventral wall of the abdomen was reflected to provide direct access
to the uterus and ovaries. The uterine artery to the pregnant horn was cannulated
with the minimum possible handling of
the uterus and perfusion was commenced.
The initial pre-wash fluid of approximately
5 ml of oxygenated bicarbonate-buffered
Krebs-Ringer (PH 7.4) was followed immediately by 1000 ml of 5% s-collidine
buffered glutaraldehyde (pH 7.2). At first
the fixative was allowed to flow unimpeded
but after about 200 rnl had been perfused,
the flow rate was reduced so that the remainder took about fifteen minutes to pass
through the organ.
Received Feb. 20, '73. Accepted June 22, '73.
1 Rockefeller Foundation Fellow in Reproductive Biology, Cambridge Universlty (1970-19711.
%Presentaddress: Dr. David W. Hamilton, DeDaxtment of Anatomy, Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115.
485
486
W. R. ALLEN, D. W. HAMILTON AND R. M. MOOR
At the end of perfusion, the uterine artery and vein were ligated and the whole
uterus was carefully removed from the animal and immersed in a pan of fixative.
The uterus was opened and visible endometrial cups and presumed areas of cup
development were carefully dissected out
with the overlying portion of allantochorion undisturbed. These pieces of tissue
were then trimmed into 1 mm3 blocks and
placed in fresh fixative at 4°C for one hour.
New razor blades were used at each stage
to minimize artifacts due to crushing.
Subsequently, the blocks were exposed
to 1% osmium tetroxide (pH 7.2, in s-collidine buffer), dehydrated and embedded
in Epon in the usual way. Sections were
cut with diamond knives and viewed with
an AEI-801 electron microscope.
OBSERVATIONS
The clearly defined sequence of events
leading to the formation of endometrial
cups is shown in figure 1. Cells from a
specialized area of the chorion, the chorionic girdle, attach to the endometrial epithelium and invade and destroy it by phagocytosis. The cells then migrate through
the basal lamina and into the endometrial
interstitium where they form definitive
cups. We will describe each stage of this
process in detail at the fine structural level.
The chorionic girdle has been observed
by others (Ewart, 1897; van Niekerk, ’65)
but its significance in cup formation has
not previously been suspected. A description of the development of the girdle and
its fine structure is essential for an understanding of its role in endometrial cup formation.
A. Development of the chorionic girdle
The foetal membranes develop relatively
late in gestation and close attachment with
the endometrium, that is placentation,
does not occur until after the 45th day of
pregnancy. Up to this stage, contact between foetal and maternal tissues is confined to a small area of bilaminar omphalopleure which persists at the abembryonic
pole of the conceptus. The allantois begins
to develop on day 21 of gestation and by
day 28 it completely surrounds the embryo
and amnion. Fusion of the allantois and
chorion gives rise to the allantochorion and
between these layers the vascular mesoderm develops. As the allantois enlarges,
the yolk sac regresses and the embryo, attached to the yolk stalk, is withdrawn towards the abembryonic pole of the conceptus (fig. 2).
At the junction of the developing allantois and regressing yolk sac, the mesoderm
is avascular and at this point the specialized chorionic girdle develops. On the 25th
day of gestation the girdle is seen as a
series of shallow corrugations of the single
layer of trophoblast cells. This folding
process increases so that by day 33, elongated closely apposed villous structures
project from the surface of the conceptus
(fig. 3). Collectively these are seen macroscopically as a discrete annulate band
around the circumference of the conceptus
(fig. 2). The allantois is not carried into
these villous projections but rather, appears to form an anchoring point for the
villi. Each villus is covered by a layer of
highly modified chorion cells and the center of the villus contains clusters of these
chorionic cells and other non-specific cellular elements. The modified chorion cells
which comprise the epithelium of the villus (“girdle cells”) are tall columnar cells
with pale nuclei. They are often binucleate
and have elongated supranuclear areas.
The intervillous spaces are filled with a
dark staining alcian-blue-positive material
which also extends over the free surface
of each villus and into the lumina of adjacent endometrial glands (fig. 4). At the
light microscopic level, this extracellular
material often has a stippled appearance
and gives the impression of an adhesive
which binds foetal and maternal surfaces
together.
B. Fine structure of girdle cells
At the electron microscopic level, the
chorionic girdle cells have many features
in common with mature endometrial cup
cells (Hamilton, Allen and Moor, ’73).
However, they also have a number of
unique features which are apparently associated with their migratory function.
These features disappear when the cells
become fully developed, sessile, endometrial cup cells.
The perinuclear regions of the highly
attenuated chorionic girdle cells contain
EQUINE ENDOMETRIAL CUPS. 11.
487
Fig. 1 Diagrammatic representation of the histogenesis of an endometrial cup. The chorionic
girdle becomes firmly attached to the endometrium and girdle cells invade and phagocytose the endometrial epithelium. The girdle cells then migrate. through the basal lamina into the endometrial stroma
where they form endometrial cup cells.
488
W. R. ALLEN, D. W. HAMILTON AND R. M. MOOR
EQUINE ENDOMETRIAL CUPS. 11.
primarily Golgi apparatus and associated
multivesicular bodies (MVB) and vesicles
(fig. 6 ) . Dictyosomes are often found completely surrounding the nucleus and, in binucleate cells, they are situated between
the nuclei. The lamellae which comprise
the Golgi are not fenestrated, but numerous uncoated and a few coated vesicles are
usually found in the same area. The MVB
have a number of curious features. In cells
situated at the center of a villus (fig. 6 )
they have a very homogeneous matrix
which in many respects resembles microbodies or peroxisomes from liver. They
contain few vesicles. However, in the chorion cells which cover the villus and are
therefore coated with extracellular material (fig. 5), the matrix of the MVB
closely resembles the extracellular material
itself (fig. 8). A comparison between the
MVB and the extracellular material is
shown in figures 7 and 8.
The basal regions of girdle cells are
identical to the basal regions of mature cup
cells (Hamilton et al., '73). They contain
profiles of short segments of endoplasmic
reticulum with ribosomes scattered over
its surface, scattered lipid droplets, mitochondria, and a ground substance containing free ribosomes and polyribosome rosettes. A representative section is shown
in figure 9.
The apical portion of the girdle cells
covering the villi is highly complex (fig.
5). A few cells exhibit a relatively uniform
microvillous border but in the majority,
the microvilli are modified to form pseudopodia of various dimensions which extend
toward the surface of the endometrium
through the layer of extracellular matrix.
Both the microvilli and the pseudopodia
Fig. 2 Intact horse conceptus at 36 days of
gestation. The arrows indicate the annulate chorionic girdle at the junction of the allantochorion
and regressing yolk sac. x 1.7.
Fig. 3a Chorionic girdle at 28 days of gestation. The single layer of elongated columnar
girdle cells is thrown into a series of shallow
ridges. x 175.
Fig. 3b Chorionic girdle at 35 days of gestation. The ridges of girdle cells have now developed into elongated, branching, villous folds
which project from the surface of the conceptus.
Many villi have been sectioned transversely. The
apical regions of the cells covering the luminal
surfaces of the villi are filled with darkly staining material. x 136.
489
are filled with fine filamentous material
(figs. 5, 10) which is similar in appearance to that found in certain areas along
the lateral cell membrane (see fig. 6, areas
of interdigitations between cells).
C . Histogenesis of endometrial cups
(i) Attachment of the chorionic girdle
to the endometrium. At 37 days of gestation, light microscopy shows uniformly
close apposition of the chorion to the endometrium. This attachment appears to be
frail and is easily disturbed except in the
region of the allantochorionic girdle. Here
the distal extremities of the elongated chorionic cells are closely moulded to the surface of the endometrial epithelium (fig.
4) so that in areas in which some disruption has occurred through rough handling,
the surfaces are mirror images of each
other.
(ii) Invasion of the endometrium by
trophoblast. The phase of attachment of
the chorionic girdle to the endometrium is
apparently of short duration, for by sampling a number of potential cups from the
same animal at 37 days of gestation, varying degrees of both migration and attachment are apparent. The first signs of invasion are seen as focal points of close
apposition between girdle cell pseudopodia
and the surface plasmalemma of endometrial epithelial cells (fig. 5). These points
of apposition then broaden into more generalized areas of cell contact with resulting
loss of surface microvilli from the endometrial cells and diminution of the extracellular material between the girdle cells
and the endometrial cells. We have not
made a detailed investigation of the nature
of the junction that forms between the two
cell types. The close apposition between
the two plasma membranes, however, is
reminiscent of the gap-type junction that
has been described in many other organs
(Revel and Karnovsky, '67).
It is surprising to find that the chorionic
cells do not invade the endometrial epithelium by way of the intercellular spaces.
Rather, they appear to pass directly down
the central axis of the epithelial cells. This
unusual process is dramaticallv demonstrated in figure 10, where a pseudopodium
from a girdle cell has intruded into the
apical cytoplasm of the epithelial cell to
490
W. R. ALLEN, D. W. HAMILTON AND R. M. MOOR
Fig. 4 In the light micrograph, the chorionic girdle is attached to the endometrial epithelium. The
villi are obvious (arrow heads) but the extracellular space is filled with a dark-staining extracellular
matrix that becomes very obvious at the mouths of the endometrial glands. x 400.
EQUINE ENDOMETRIAL CUPS. 11.
49 1
Fig. 5 At the electron microscopic level one can appreciate the major fine structural features of the
girdle cells. The amoeboid apical surface of the girdle cells, and the fine filamentous nature of the
amoeboid processes, is contrasted sharply with the less develooed surface of endometrial epithelial
cells. Note that the extracellular matrix is a t times present in apical vacuoles of the endometrial cells.
X 11,790.
492
W. R. ALLEN, D. W. HAMILTON AND R. M. MOOR
Fig. 6 Chorionic girdle cells are elongate and narrow, a s shown here, with complex lateral intercellular relationships. Note the texture of the cytoplasm in the intercrescent folds. x 10,900.
EQUINE ENDOMETRIAL CUPS. 11.
493
Figs. 7-8 In these two micrographs, the texture of the matrix of multivesicular bodies (fig. 7) is
contrasted with the extracellular matrix (fig. 8). The areas of rarefaction contain short anastomosing
filaments. These areas produce a stippling effect at the light microscope level. x 34,000.
494
W. R. ALLEN, D. W. HAMILTON AND R. M. MOOR
Fig. 9 The general cytoplasm of girdle cells is composed of profiles of tubular and vesicular rough
endoplasmic reticulum, scattered mitochondria and numerous granules (presumably ribosomal in nature). x 14,460.
EQUINE ENDOMETRIAL CUPS. 11.
495
Fig. 10 The initial stage of invasion by the girdle cells is represented here. Girdle cell processes
protrude dramatically directly into the cytoplasm of the endometrial epithelial cells and do not enter
the intercellular space. x 14,290.
496
W. R. ALLEN, D. W. HAMILTON AND R. M. MOOR
Figs. 11-12 As girdle cells proceed through the epithelial layer they sequester the epithelial cells
(fig. 1 1 ) and eventually phagocytose them (fig. 12). X 9500.
EQUINE ENDOMETRIAL CUPS. 11.
497
Fig. 13 The girdle cells eventually extend their processes ( P ) through the basal lamina (arrow
heads) and enter the interstitium of the endometrium. x 15,600.
498
W. R. ALLEN, D. W. HAMILTON AND R. M. MOOR
Fig. 14 Wandering macrophages in the endometrial interstitium phagocytose collagen fibrils. In
this illustration, collagen can be recognized in multivesicular bodies throughout the cytoplasm of the
cell. x 42,000.
499
EQUINE ENDOMETRIAL CUPS. 11.
the extent that the shape of the nucleus
is affected.
(iii) Phagocytosis of the endometrial
epithelium. Intermediate stages between
the processes of invasion of the chorionic
girdle cells into the endometrial epithelium
and their eventual migration into the interstitium are difficult to find. At the light
microscopic level, endometrial epithelial
cells being invaded by chorionic girdle
cells are clearly visible in one area of a
developing cup while in adjacent areas of
the same cup, the endometrial epithelial
cells have already disappeared. This is a
further indication of the rapidity of the
invasion process. A t the electron microscopic level, it is clear that the invading
cells of the chorion sequester the epithelial
cells (fig. 11) and eventually phagocytose
them (fig. 12).
(iv) Invasion of the endometrial stroma.
The final stage in the formation of the endometrial cups involves penetration of the
basal lamina of the endometrial epithelium
by the invading chorionic cells and passage
of the latter into the endometrial stroma.
This is accomplished in the same way as
the original invasion of the endometrial
epithelium; pseudopodia force their way
through the basal lamina, followed by the
remainder of the cell. During the phagocytic phase of the invasion process, the
pseudopod extensions are as numerous as
in the early stages (fig. 11) and small
processes from these are commonly found
extending through the basal lamina (fig.
13). Larger processes are also present in
the interstitium surrounded by densely
packed collagen fibers (fig. 13).
The endometrial stroma contains numerous fibroblasts and wandering stromal
cells and just prior to girdle cell invasion,
it is packed with large amounts of collagen.
Relatively little collagen is found in the
fully developed endometrial cup, however
(Hamilton et al., '73). This decrease in
collagen can probably be ascribed to the
presence of numerous phagocytic cells in
the interstitium which appear to be selective for collagen fibrils. One such cell, containing sequestered collagen in multivesicular-like, membrane-bounded vacuoles, is
seen in figure 14.
The processes of direct invasion and
phagocytosis of epithelial cells described
above occur only in the epithelium on the
surface of the endometrium. In contrast,
uterine gland epithelium is not attacked
in the same manner and the invading
chorionic girdle cells migrate down the
length of the glands between the epithelial
cells and their basal laminae without damaging or phagocytosing the epithelial cells.
The girdle cells then pass through the basal
lamina and into endometrial stroma where
they cease to migrate, hypertrophy, and assume the epithelioid appearance of mature
cup cells.
DISCUSSION
Although early stages of formation of
the chorionic girdle have not been thoroughly studied, it is nevertheless clear that
the girdle develops entirely from the chorion and contains no allantoic elements.
Whether girdle development proceeds by
specialization (or maturation) of preformed
chorionic cells, or by production of new
cells, is not clear. There are only slight
structural differences between normal chorion cells that wdl go on to form the
allantochorionic placenta and those that
form the chorionic girdle prior to invasion. Both cells are tall, columnar in type
and have amoeboid-like free surfaces.
Each contains approximately the same
amounts of the same cell organelles and
all the chorion cells seem able to produce
the alcian-blue staining extracellular material which presumably helps to bind
foetal and maternal surfaces together. The
one outstanding feature of the girdle cells
is a large euchromatic nucleus with an immense nucleolus. This feature alone could
perhaps account for the unique physiological properties of the chorionic girdle, for
it implies a significant difference between
nuclear-directed activities in the two populations of cells.
The intracellular source of the acidic
extracellular material is of some interest
because of the close resemblance between
this material and the matrix of the multivesicular bodies in the girdle cells. The
striking similarity between the two provides only circumstantial evidence for a
causal relationship between them. There is,
however, some other evidence to indicate
500
W. R. ALLEN, D. W. HAMILTON AND R. M. MOOR
that MVBs and lysosomes are active either
in the digestion of extracellular material
(Friend, '69) or in the elaboration of some
of the acid hydrolases destined to be secreted by some cells (Dingle, '69; Helminnen and Ericsson, '72). It is therefore
tempting to speculate that the extracellular material is secreted by the MVB of the
girdle cells and that the material aids in
the digestion of endometrial epithelial cell
debris. Many electron micrographs show
profiles of membrane debris located at the
surfaces of endometrial epithelial cells in
the extracellular space (fig. 5). It seems
likely that these represent an initial stage
in the breakdown of the epithelial plasmalemma as a result of the action of extracellular enzymes (lipases or proteinases)
secreted by the girdle cells.
An alternative explanation for the resemblance between MVB matrix and extracellular material is that the latter is being
digested by the girdle cells. This explanation would agree with the results of studies
on the uptake of exogenous tracers by
other cell systems (see reviews in Dingle
and Fell, '69). However there are very few
coated vesicles present in chorionic girdle
cells and these are considered to be essential for micropinocytosis of macromolecules (Friend and Farquhar, '67).
The occurrence of alcian-blue-positive
material as an extracellular matrix
strongly suggests the presence of acid
mucopolysaccharides. Bernfield and Banerjee ('72) and Bernfield et al. ('72) demonstrated that the extracellular acidic glycosaminoglycans play a major role in the developmental processes which determine
branching patterns in mouse embryonic
salivary glands. There is also evidence to
indicate the importance of mucopolysaccharides in developmental processes in
other systems (Manasek, '70). It is possible therefore that dependence upon extracellular mucopolysaccharides is a widespread phenomenon and that, as well as
functioning as a means of attachment, the
extracellular matrix may be involved in
determining the developmental sequence
of the invasion of the endometrium by
chorionic girdle cells.
By whatever means the chorionic girdle
attaches to the endometrium, it is clear
that active invasion of girdle cells occurs
only after close apposition of the plasmalemma of the girdle cell with that of the
epithelial cell. Our findings suggest that a
gap junction (Revel and Karnovsky, '67)
may form between these two cell types.
Gap junctions are considered to be sites of
low resistance contact between cells (see
Goodenough and Stoeckenius, '72, for references) and they may be involved in
synchronizing metabolic activity in large
populations of similar cells. It is also
possible that this type of junction is involved in signals between different cell
types. Thus in the pregnant mare, it would
be important for the foetal and maternal
cells to be functionally as well as structurally interrelated, especially at the commencement of the invasion process. Such
junctional specialization may therefore
represent the earliest indication that implantation is about to occur.
The morphological features normally associated with cell motility are abundantly
represented in girdle cells. The amoeboidlike cell surface and the ectoplasmic layer
of fine filaments are both features which
are commonly found in actively moving
cells. The feltwork nature of the f2aments seen in girdle cells (figs. 11, 12) is
quite different from the discrete bundles
of filaments which are described by other
workers in cells such as neurulating ectoderm (Burnside, '71) and in fibroblasts
(Buckley and Porter, '67). Indeed, they
differ from the extensive development of
filaments seen in fully developed endometrial cup cells (Hamilton et al., '73).
However, the filamentous feltwork in chorionic girdle cells does closely resemble
the ectoplasmic microfilaments present in
growth cones of elongating axons and in
migrating glial cells which Wessells et al.
('70) have shown to be involved in cell
motility. It would be of interest to determine whether or not cytochalasin B, a compound that is known to affect intracellular
microfilaments and cell motility (Wessells
et al., '71), would prevent formation of
endometrial cups in the mare.
Our findings have demonstrated conclusively that endometrial cups in the mare
are derived from specialized foetal trophoblast cells by a process which is summarized in figure 1. We have shown elsewhere
that explants of these cells secrete gonado-
EQUINE ENDOMETRIAL CUPS. 11.
trophins when cultivated in vitro and when
grafted allogeneically (Allen and Moor,
'72). Thus, it would appear that Equidae
are similar to humans and other primates
in which trophoblast cells also invade the
endometrium and produce gonadotrophin.
There are significant differences however;
in the mare, the invading trophoblast cells
become completely detached from the remaining foetal membranes and they enter
the endometrium some ten days before the
true allantochorionic placenta is established. They remain as a discrete colony
of single cells in the endometrium and do
not form a syncytium. Furthermore, the
invasion of lymphocytes and plasma cells
which ultimately leads to the premature
necrosis of the cups and their rejection
from the endometrium, strongly suggests
that the invading chorionic girdle cells express foetal transplantation antigens which
are immLmologically recognized by the
mare.
ACKNOWLEDGMENTS
We are grateful to Professor T. R. R.
Mann and Professor D. Fawcett for their
helpful criticisms of the manuscript. Financial support for this work was provided
by the Thoroughbred Breeders Association
and by the Rockefeller Foundation.
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